The compound of formula I, depicted below, has been reported by Clark, International Patent Publication WO 89/08651 (now U.S. Pat. No. 5,036,079), to be a potent hypoglycemic in mammals. ##STR1##
A key intermediate in the synthesis of this compound is the compound of formula II, depicted below, which has a bromo atom poised for conversion into the thiazolidinylmethyl moiety of the final product. ##STR2##
This compound has previously been prepared by reduction of the precursor ketone of formula III and subsequent diastereomeric resolution of the racemic alcohol as reported by Clark (vide supra). This resolution, while ##STR3## generally affording a high degree of optical purity, is a time-consuming, two-step process which, even under the best of circumstances, gives only a 50% yield of the desired product from the starting ketone.
The process of the present invention solves this problem by performing the reduction of the ketone under conditions which generate alcohol (II) in optically pure form. The process also lends itself to preparation of the corresponding (R) enantiomer, likewise in optically pure form.
The stereoselective reduction process of this invention involves the use of a borane reducing agent and a chiral oxazaborolidine catalyst. Corey, et al. (Journal of the American Chemical Society, 1987, 109, 5551-3 and 7925-6) have described generally the reduction of a limited number of ketones with boranes utilizing chiral oxazaborolidines to elicit enantioselectivity. However, recent studies by Jones, et al. (Journal of Organic Chemistry, 1991, 56, 763-9) have demonstrated that the method loses its effectiveness when molecules possessing borane coordination sites are present in the reaction mixture. Examples of compounds containing borane coordination sites include but are not limited to such compounds as boronic acids, boroxines, prolinols, amines, thiazoles and oxazoles. This loss of effectiveness is manifested in diminished enantioselectivity. The present invention is directed to a process in which the deleterious effect of said borane coordination sites has been overcome.